title: 20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension.
abstract: 20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 (Cyp)-derived arachidonic acid metabolite that has been shown to increase smooth muscle contractions and proliferation, stimulate endothelial dysfunction and activation, and promote hypertension. We examined if 20-HETE contributes to microvascular remodeling in hypertension. In Sprague-Dawley rats, administration of the 20-HETE biosynthesis inhibitor HET0016 or the 20-HETE antagonist N-20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) prevented 5α-dihydrotestosterone (DHT)-induced increases in blood pressure as well as abrogated DHT-induced increases in the media-to-lumen ratio (M/L), media thickness, and collagen IV deposition in renal interlobar arteries. Reserpine prevented blood pressure elevation in DHT-treated rats but did not affect microvascular remodeling (M/L, media thickness, and collagen deposition); under these conditions, treatment with the 20-HETE antagonist attenuated microvascular remodeling, suggesting that 20-HETE contributes to DHT-induced vascular remodeling independent of blood pressure elevation. In Cyp4a14(-/-) mice, which display androgen-driven and 20-HETE-dependent hypertension, treatment with the 20-HETE antagonist abolished remodeling of renal resistance arteries measured as media thickness (24 ± 1 vs. 15 ± 1 μm) and M/L (0.29 ± 0.03 vs. 0.17 ± 0.01). Moreover, in Cyp4a12 transgenic mice in which the expression of Cyp4a12-20-HETE synthase is driven by a tetracycline-sensitive promoter, treatment with doxycycline resulted in blood pressure elevation (140 ± 4 vs. 92 ± 5 mmHg) and a significant increase in remodeling of renal resistance arteries (media thickness: 23 ± 1 vs. 16 ± 1 μm; M/L: 0.39 ± 0.04 vs. 0.23 ± 0.02); these increases were abrogated by cotreatment with 20-HEDE. This study demonstrated that 20-HETE is a key regulator of microvascular remodeling in hypertension; its effect is independent of blood pressure elevation and androgen levels.
authors.affiliation: 1Department of Pharmacology, New York Medical College, 15 Dana Road, BSB Rm. 530, Valhalla, NY 10595, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Wu
authors.forename: Victor
authors.initials: V
authors.lastname: Garcia
authors.forename: Irina
authors.initials: I
authors.lastname: Dimitrova
authors.forename: Adam
authors.initials: A
authors.lastname: Weidenhammer
authors.forename: Gregory
authors.initials: G
authors.lastname: Joseph
authors.forename: Frank
authors.initials: F
authors.lastname: Zhang
authors.forename: Vijay L
authors.initials: VL
authors.lastname: Manthati
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Capdevila
authors.forename: Michal L
authors.initials: ML
authors.lastname: Schwartzman
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D013196:Dihydrotestosterone; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000187:drug effects* / Q000503:physiopathology; D012110:Reserpine / Q000494:pharmacology
chemical_list: C494667:20-hydroxyeicosa-6(Z),15(Z)-dienoic acid; D006893:Hydroxyeicosatetraenoic Acids; D013196:Dihydrotestosterone; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D012110:Reserpine
keywords: 20-hydroxyeicosatetraenoic acid; androgen; blood pressure; cytochrome P-450 4A